New hyperekplexia mutations provide insight into glycine receptor assembly, trafficking, and activation mechanisms

Background: Hyperekplexia mutations have provided much information about glycine receptor structure and function. Results: Weidentified and characterized nine new mutations. Dominant mutations resulted in spontaneous activation, whereas recessive mutations precluded surface expression. Conclusion: These data provide insight into glycine receptor activation mechanisms and surface expression determinants. Significance: The results enhance our understanding of hyperekplexia pathology and glycine receptor structure-function. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A

Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy

AbstractDevelopmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients’ primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy.</jats:p

Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy

Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients’ primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy

Functional and quality of life outcomes of localised prostate cancer treatments (prostate testing for cancer and treatment [ProtecT] study)

Objective To investigate the functional and quality of life (QoL) outcomes of treatments for localised prostate cancer and inform treatment decision-making. Patients and Methods Men aged 50–69 years diagnosed with localised prostate cancer by prostate-specific antigen testing and biopsies at nine UK centres in the Prostate Testing for Cancer and Treatment (ProtecT) trial were randomised to, or chose one of, three treatments. Of 2565 participants, 1135 men received active monitoring (AM), 750 a radical prostatectomy (RP), 603 external-beam radiotherapy (EBRT) with concurrent androgen-deprivation therapy (ADT) and 77 low-dose-rate brachytherapy (BT, not a randomised treatment). Patient-reported outcome measures (PROMs) completed annually for 6 years were analysed by initial treatment and censored for subsequent treatments. Mixed effects models were adjusted for baseline characteristics using propensity scores. Results Treatment-received analyses revealed different impacts of treatments over 6 years. Men remaining on AM experienced gradual declines in sexual and urinary function with age (e.g., increases in erectile dysfunction from 35% of men at baseline to 53% at 6 years and nocturia similarly from 20% to 38%). Radical treatment impacts were immediate and continued over 6 years. After RP, 95% of men reported erectile dysfunction persisting for 85% at 6 years, and after EBRT this was reported by 69% and 74%, respectively (P < 0.001 compared with AM). After RP, 36% of men reported urinary leakage requiring at least 1 pad/day, persisting for 20% at 6 years, compared with no change in men receiving EBRT or AM (P < 0.001). Worse bowel function and bother (e.g., bloody stools 6% at 6 years and faecal incontinence 10%) was experienced by men after EBRT than after RP or AM (P < 0.001) with lesser effects after BT. No treatment affected mental or physical QoL. Conclusion Treatment decision-making for localised prostate cancer can be informed by these 6-year functional and QoL outcomes

Payment history, past returns and the performance of UK zero dividend stocks

Purpose: A growing strand of literature has focused on the returns performance of zero dividend stocks. This paper seeks to provide new evidence on the link between dividend payment and returns history and firms’ subsequent stock market performance.Design/methodology/approach: Prior research draws a distinction between those stocks which have never paid dividends and those which formerly paid dividends but subsequently ceased, implicitly using the latter as a measure of financial distress. The analysis is expanded beyond the role of payment history, and also the importance of earnings and past returns in the performance of UK zero-dividend stocks is considered.Findings: In contrast with the prior US evidence, it was found that payment history is not a significant determinant of returns, while past returns play a far greater role. However, this explanatory power seems to be diminishing over time.Research limitations/implications: The paper extends the existing knowledge about the behaviour of UK zero dividend stocks and establishes a benchmark for future research in the area.Practical implications: The prevalence of zero dividend stocks has grown over time. In the US, the proportion of listed companies paying dividends fell from 66.5 per cent in 1978 to only 20.8 per cent in 1999. In the UK, the proportion of companies omitting dividends rose to 25.2 per cent in 1999, from previous recession-year high points of 16.1 per cent in 1982 and 17.9 per cent in 1992. This paper provides new evidence of practical value to investors in this class of stocks.Originality/value: The paper presents original research in the area of dividend policy and stock returns, which should be of interest to both academic and practitioner audiences

Payment history, past returns and the performance of UK zero dividend stocks

Purpose: A growing strand of literature has focused on the returns performance of zero dividend stocks. This paper seeks to provide new evidence on the link between dividend payment and returns history and firms’ subsequent stock market performance.<br/>Design/methodology/approach: Prior research draws a distinction between those stocks which have never paid dividends and those which formerly paid dividends but subsequently ceased, implicitly using the latter as a measure of financial distress. The analysis is expanded beyond the role of payment history, and also the importance of earnings and past returns in the performance of UK zero-dividend stocks is considered.<br/>Findings: In contrast with the prior US evidence, it was found that payment history is not a significant determinant of returns, while past returns play a far greater role. However, this explanatory power seems to be diminishing over time.<br/>Research limitations/implications: The paper extends the existing knowledge about the behaviour of UK zero dividend stocks and establishes a benchmark for future research in the area.<br/>Practical implications: The prevalence of zero dividend stocks has grown over time. In the US, the proportion of listed companies paying dividends fell from 66.5 per cent in 1978 to only 20.8 per cent in 1999. In the UK, the proportion of companies omitting dividends rose to 25.2 per cent in 1999, from previous recession-year high points of 16.1 per cent in 1982 and 17.9 per cent in 1992. This paper provides new evidence of practical value to investors in this class of stocks.<br/>Originality/value: The paper presents original research in the area of dividend policy and stock returns, which should be of interest to both academic and practitioner audiences